A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus

Tang, Shao Jun; Reis, Gerald; Kang, Hyejin; Gingras, Anne-Claude; Sonenberg, Nahum; Schuman, Erin M.

doi:10.1073/pnas.012605299

Cited by 734Neuroscience and Neuropharmacology ResearchPI3K/AKT/mTOR signaling in cancerMemory and Neural Mechanisms

A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus

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Tang, Shao Jun, Reis, Gerald, Kang, Hyejin, Gingras, Anne-Claude, Sonenberg, Nahum, Schuman, Erin M.·2002·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.012605299PMC PMC117583

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Abstract

Many forms of long-lasting behavioral and synaptic plasticity require the synthesis of new proteins. For example, long-term potentiation (LTP) that endures for more than an hour requires both transcription and translation. The signal-transduction mechanisms that couple synaptic events to protein translational machinery during long-lasting synaptic plasticity, however, are not well understood. One signaling pathway that is stimulated by growth factors and results in the translation of specific mRNAs includes the rapamycin-sensitive kinase mammalian target of rapamycin (mTOR, also known as FRAP and RAFT-1). Several components of this translational signaling pathway, including mTOR, eukaryotic initiation factor-4E-binding proteins 1 and 2, and eukaryotic initiation factor-4E, are present in the rat hippocampus as shown by Western blot analysis, and these proteins are detected in the cell bodies and dendrites in the hippocampal slices by immunostaining studies. In cultured hippocampal neurons, these proteins are present in dendrites and are often found near the presynaptic protein, synapsin I. At synaptic sites, their distribution completely overlaps with a postsynaptic protein, PSD-95. These observations suggest the postsynaptic localization of these proteins. Disruption of mTOR signaling by rapamycin results in a reduction of late-phase LTP expression induced by high-frequency stimulation; the early phase of LTP is unaffected. Rapamycin also blocks the synaptic potentiation induced by brain-derived neurotrophic factor in hippocampal slices. These results demonstrate an essential role for rapamycin-sensitive signaling in the expression of two forms of synaptic plasticity that require new protein synthesis. The localization of this translational signaling pathway at postsynaptic sites may provide a mechanism that controls local protein synthesis at potentiated synapses.

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mTORC1 tightly coordinates LTP and LTD, the molecular correlates of learning and memory.
“In the brain, mTORC1 tightly coordinates different synaptic plasticities -long-term potentiation (LTP) and long-term depression (LTD) -the molecular correlates of learning and memory (2)(3)(4)(5).”
From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [2]
The Results report that rapamycin inhibited late-phase LTP in hippocampal slices but left early-phase LTP unaffected; the Discussion also links LTP to long-term information storage. The paper does not report an effect on LTD or establish that mTORC1 tightly coordinates both LTP and LTD. (LLM, conf=0.88)
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Synaptic tagging and long-term potentiation
Frey, U., & Morris, R. G. M. (1997) · Nature · doi:10.1038/385533a0 · Cited by 1,736 · see citing works
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Authors: Tang, S. J., Reis, G., Kang, H., Gingras, A.-C., Sonenberg, N., & Schuman, E. M.
Affiliations: California Institute of Technology (US)
ORCID: Reis, Gerald
Gingras, Anne-Claude
Sonenberg, Nahum
Schuman, Erin M.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2001-12-26
Volume: 99
Issue: 1
Pages: 467-472
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.012605299
PMC: PMC117583
OpenAlex: W2056994440
Cited by: 734
References: 3
Citations by year: 2026: 16 · 2025: 17 · 2024: 12 · 2023: 25 · 2022: 18 · 2021: 29 · 2020: 35 · 2019: 29 · 2018: 24 · 2017: 34 · 2016: 27 · 2015: 38 · 2014: 44 · 2013: 52 · 2012: 51
FWCI: 6.65
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
CaltechAUTHORS (California Institute of Technology) (submittedVersion)
eScholarship@McGill (McGill) (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords: mTOR signaling, rapamycin, synaptic plasticity, long-term potentiation, hippocampus, protein synthesis, eIF4E, eIF4E-binding protein, PSD-95, synapsin I, brain-derived neurotrophic factor, postsynaptic localization, dendrites, translational regulation
MeSH terms: Disks Large Homolog 4 Protein, Animals, Antibiotics, Antineoplastic, Carrier Proteins, Electrophysiology, Female, Hippocampus, Immunoglobulin G, Male, Membrane Proteins, Mice, Inbred C57BL, Microscopy, Fluorescence, Nerve Tissue Proteins, Peptide Initiation Factors, Phosphoproteins, Protein Binding, Protein Kinases, Synapses, Time Factors, Protein Biosynthesis, Blotting, Western, Signal Transduction, Rats, Sprague-Dawley, Cell Cycle Proteins, Sirolimus, Eukaryotic Initiation Factor-4E, Eukaryotic Initiation Factors, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Rats, Guanylate Kinases, TOR Serine-Threonine Kinases

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A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus

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